Conversion to everolimus monotherapy in maintenance liver transplantation: feasibility, safety, and impact on renal function

Conversion to everolimus monotherapy in maintenanceliver transplantation: feasibility, safety, and impacton renal functionPaolo De Simone,1 Paola Carrai,1 Arianna Precisi,2 Stefania Petruccelli,1 Lidiana Baldoni,1 EmanueleBalzano,1 Juri Ducci,1 Francesco Caneschi,3 Laura Coletti,1 Daniela Campani4 and Franco Filipponi1 1 Unita` Operativa Chirurgia Generale e Trapianti di Fegato, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy2 Laboratorio, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy3 Unita` Operativa Gastroenterologia, Ospedale San Donato, Arezzo, Italy4 Anatomia Patologica, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy calcineurin inhibitors, everolimus,immunosuppression, liver transplantation.
We present the 12-month results of a prospective trial of conversion fromcalcineurin inhibitors (CNI) to everolimus (EVL) in maintenance liver trans- plant (LT) recipients. Forty (M:F = 28:12; 54.9 ± 11 years) patients were Franco Filipponi MD, PhD, Unita` Operativa enrolled at a mean interval of 45.5 ± 31.2 months from transplantation. Con- Chirurgia Generale e Trapianti di Fegato, version was with EVL at a dosage of 0.75 mg b.i.d., withdrawal of antimetabo- Azienda Ospedaliero-Universitaria Pisana, lites, and a 50%-per-week reduction of CNI to a complete stop within 4 weeks.
Ospedale Cisanello, Via Paradisa, 2, 56124Pisa, Italy. Tel.: +39 050 99 54 21; fax: The treatment success was conversion to EVL monotherapy at 12 months while +39 050 99 54 20; e-mail: f.filipponi@med.
failure was presence of CNI, death, and graft loss. Indication to conversion was deteriorating renal function in 36 (90%). At 12 months, patient- and graft sur-vival were 100% and the success rate was 75% (30/40). Ten patients (25%) were failures: four (10%) for acute rejection; three hepatitis C virus-RNA posi- tive patients (7.5%) for hypertransaminasemia; one (2.5%) for acute cholangi- tis; and two (5%) due to persistent pruritus and oral ulcers. In patients on EVL monotherapy, at 12 months the mean change of calculated creatinineclearance (cCrCl) was 4.03 ± 12.6 mL/min and the only variable correlatedwith the probability of improvement was baseline cCrCl (P < 0.0001). Conver-sion from CNI to EVL is feasible in 75% of the cases and associated withimprovement in renal function for patients with higher baseline cCrCl.
for acute rejection [6–8]. Everolimus (EVL) belongs to a novel class of immunosuppressants – the proliferation Use of calcineurin inhibitors (CNI) as main immuno- signal inhibitors (PSI) [9] – whose renal sparing profile suppressants in solid organ transplantation is associated make them a promising alternative in solid organ with reduced risk of rejection but early and long-term related side-effects [1]. CNI can contribute to reduced demonstrated that EVL enhances immunosuppression in levels of renal function [2], neurotoxicity [3], increased CsA-based regimens [10,11]. A phase I study in liver cardiovascular risk [4] and incidence of post-transplant diabetes mellitus [5]. However, elimination of cyclospor- administration of EVL, micrcoemulsion CsA (CsA-ME) ine (CsA) or tacrolimus (TAC) in the early post-trans- and steroids (S) was not associated with significant changes in clinical parameters or increased rates of immunosuppressive strategies without increasing the risk infections [12]. A recent, phase II trial on fixed doses of ª 2008 The AuthorsJournal compilation ª 2008 European Society for Organ Transplantation 22 (2009) 279–286 EVL and CsA-ME in de novo LT recipients provided incidence of serious adverse events. Treatment success was further evidence supporting the efficacy and safety of defined as percent of patients at 12 months alive, with a EVL in this category of patients [13]. Furthermore, functioning graft and on EVL monotherapy, while the in vitro and in vivo studies have demonstrated that EVL treatment failure was persistence of CNI four weeks of EVL inhibits cell growth and proliferation by blockage of the initiation, needed for dialysis, CNI reintroduction, graft mammalian target of rapamycin [14–16], attracting loss and death. The study secondary objective was to assess interest in the use of this drug for treatment and pre- whether conversion to CerticanÒ monotherapy improved vention of post-transplant malignancies [17].
renal function by assessment of the change in the calcu- Preliminary experiences on the use of PSI in main- lated CrCl from baseline ()day 1 before EVL initiation) tenance LT have mainly focused on sirolimus (SRL) in to month 12. The study was carried out at the Unita` patients affected with CNI-related renal impairment Operativa Chirurgia Generale e Trapianti di Fegato of the [18–27]. These studies have demonstrated that CNI mini- Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy in mization with SRL or conversion from CNI-based to cooperation with the Laboratory Department. Enrollment SRL-based immunosuppression is feasible, and associated aimed at maintenance, LT patients with a minimum fol- with a 5–15% risk for acute rejection, and a variable low-up of 12 months and: a calculated CrCl (cCrCl) degree of improvement in renal function depending on according to Cockroft and Gault [28] between 80 and the baseline creatinine clearance (CrCl) [23,27], concur- 20 ml/min (stage II–IV of the National Kidney Founda- rent non-CNI-related renal disease [25], and interval from transplantation [25,27]. However, two small, prospective, cCrCl ‡ 81 ml/min in the presence of anti-hypertensive randomized, single-center trials on conversion to SRL medication, chronic ischemic cardiomyopathy, insulin- versus CNI continuation in patients with impaired renal dependent diabetes mellitus, either pre-existing or de novo function have recently demonstrated that CNI withdrawal post-transplantation (fasting blood glucose ‡ 7 mmol/l); is associated with a significant improvement in CrCl noninsulin-dependent diabetes mellitus, either pre-existing 3 months after switch, but not at 12 months, suggesting or de novo post-transplantation (fasting blood glu- that earlier CNI minimization be the key to prevention of cose ‡ 7 mmol/l); peripheral arteriopathy (‡grade II); the post-transplant decline in renal function in LT patients prior or active neurological disease (as for epilepsy, prior [25,26]. This study was performed to explore the feasibil- stroke, prior neurosurgery, etc.), for whom conversion to ity of conversion to EVL with discontinuation of CNI in EVL was perceived to be protective against the decline in adult, maintenance LT recipients with a minimum follow- renal and/or neurological functions. Eligible patients had up of 12 months, CNI-related renal impairment or at risk to be on CNI-based immunosuppression, either with TAC of neurological and renal complications. The secondary with C0-h level between 3 and 8 ng/ml or CsA-ME with objectives were to assess the impact of conversion to EVL C0-h level £ 150 ng/ml and/or C2-h level within 650 ng/ on renal function and derive information for refinement ml with or without any of the following: mycophenolate of the mode and timing of introduction of EVL.
mofetil (MMF), mycophenolic acid (MPA), azathioprine(AZA) or S. Only patients willing and capable of givingwritten informed consent for study participation and able to participate in the study for at least 12 months were The study was designed to evaluate the feasibility of con- enrolled. Exclusion criteria called for: recipients of multiple version to EVL (CerticanÒ, Novartis, Basel, Switzerland) solid organ transplants; patients with a cCrCl ‡ 81 ml/min with discontinuation of CNI within 4 weeks of CerticanÒ in the absence of coexisting morbidities and/or risk factors initiation in adult, maintenance LT recipients with a mini- indicated above; patients on dialysis; patients with protein- mum follow-up of 12 months and CNI-related renal uria ‡ 1.0 g/24 h; patients with any acute rejection within impairment or at risk of neurological and renal complica- 6 months prior to randomization; a platelet count of tions, while maintaining efficacy. This was evaluated by £50 000/mm3 or white blood cell count of £2000/mm3 or efficacy and safety parameters within 12 months of Certi- hemoglobin £ 8 g/dl; patient with graft dysfunction as canÒ initiation by: incidence of efficacy failure [biopsy- clinically indicated or associated with bilirubin >2 mg/dl, proven acute rejection (BPAR), graft loss or death]; or albumin <35 g/l (in the absence of proteinuria) or pro- incidence of treated BPAR; incidence and reasons for fail- thrombin time >1.3 INR (in the absence of anticoagulant ure; patient- and graft survival; safety parameters, includ- medication); HCV positive patients requiring an active anti-viral treatment; HIV positive patients; breast feed- anemia; infections; hepatitis C virus (HCV) load, and ing females; patients with concurrent severe systemic malignancies; incidence of discontinuation of study medi- infection; presence of any hypersensitivity to drugs simi- cation; incidence of premature study withdrawal; and lar to CerticanÒ (e.g. macrolides); and use of any Journal compilation ª 2008 European Society for Organ Transplantation 22 (2009) 279–286 immunosuppressive drugs other than PrografÒ/NeoralÒ, S, Table 1. Demographic characteristics of the study population at MMF, MPA, and AZA. Once written informed consent was signed, patients were screened to evaluate for eligibility into the study. Screening assessments occurred at least12 months after LT. Patients who satisfied the inclusion and exclusion criteria were administered EVL at a dosage of 0.75 mg b.i.d. (1.5 mg/daily) starting on day 1 and CNI were decreased by 50% per week when EVL was initiated.
MMF, MPA and AZA were discontinued upon EVL initia- tion. Steroids were maintained at preswitch levels. EVL dosage was adjusted throughout the study in order to achieve a recommended trough level between 3 and 8 ng/ ml (FPIA) according to liver function tests and incidence of adverse events. Levels below 3 ng/ml and higher than 8 ng/ml were based on proven clinical indications, occur- rence of adverse event(s), and/or lack of efficacy. CNI were decreased each week by 50% of the current dose or so as to allow CNI discontinuation within 4 weeks of EVL initia- tion, unless otherwise clinically indicated. The study dura- tion was 12 months after EVL initiation. Patients visits were scheduled within 4 weeks prior to day )1, at day )1, week 1, week 2, week 3, week 4 and months 2, 3, 4, 5, 6 and 12. Once suspected, acute rejection was to be con- firmed by biopsy and graded according to the 1997 Banff classification (RAI scoring system) [30]. We decided to treat rejection episodes with a RAI score < 7 with EVL dose adjustments and those with a RAI score ‡ 7 with either pulse steroids, CNI reintroduction/dose adjustments or a combination thereof. Data management was according Between October 1st 2006 and May 31st 2007 a total of PBC, primary biliary cirrhosis; CHC, cholangiocellular carcinoma; cCrCl, 40 patients (mean age 54.9 ± 11 years; M/F = 28/12) were calculated creatinine clearance according to Cockroft–Gault.
enrolled at a mean of 45.5 ± 31.2 months post-LT. Native *Baseline is )Day 1 before EVL initiation.
disease was HCV-related chronic failure in 15 (37.5%); HBV-related in 10 (25%); alcohol-related in eight (20%);primary biliary cirrhosis in four (5%); Wilson’s disease,polycystic liver and cholangiocarcinoma in one patient and TAC with S and antimetabolites in one (2.5%) each.
(2.5%) each (Table 1). All of the 15 HCV patients were At baseline, mean CsA-ME daily dosage was 131.8 ± 39.8 PCR-RNA positive at the time of switching and viral vs. 3.1 ± 1.7 mg for TAC; mean CsA trough level was genotype was one in all such cases. Eleven patients 92.1 ± 43.8 ng/ml; mean CsA C2-h level was 435.4 ± (27.5%) were concomitantly affected with hepatocellular carcinoma (nine within Milan and two beyond Milan on 6.7 ± 1.3 ng/ml. As for renal function, mean cCrCl was explant histology) (Table 1). Indications for conversion 60.6 ± 23 ml/min and mean proteinuria (spot sample) CNI-related peripheral neuropathy in three (7.5%), and Twelve months after conversion, patient and graft sur- CNI-related microangiopathy in one (2.5%). At baseline vival was 100%. The treatment success rate (i.e. CNI (1 day before EVL initiation), patients’ immunosuppres- elimination) was 75% (30/40). Ten patients (25%) were sion was: CsA-ME alone in 16 cases (40%); CsA-ME in treatment failures: namely, six (15%) patients discontin- association with antimetabolites in 12 (30%); TAC alone ued EVL because of adverse effects, while four (10%) for in nine (22.5%); TAC with antimetabolites, TAC with S, BPAR (Table 2). Incidence of treated BPAR was 15% ª 2008 The AuthorsJournal compilation ª 2008 European Society for Organ Transplantation 22 (2009) 279–286 (6/40). Rejection episodes occurred at a mean of 2.32 ng/ml in patients with no BPAR (p = 0.8562). The 70 ± 14.1 days after EVL initiation with a mean RAI complications observed in the entire population of score of 7 ± 0.6. BPAR was treated with CNI reintroduc- patients who received at least one dose of the study drug tion in three (7.5%) cases; EVL dose adjustment in two (40/40) are listed in Table 2 and included: hyperlipemia (5%); and steroid boluses and resumption of previous CNI-based therapy (TAC, S, AZA) in one case (2.5%) rides > 350 mg/dl) in 17 patients (42.5%); mouth sores (Table 2). In patients with BPAR, mean EVL blood level in nine (22.5%); hypertransaminasemia ‡ 3 times the until the time of diagnosis was 4.9 ± 2.4 vs. 5.03 ± upper limit of the range in three HCV-RNA positivepatients (7.5%); pruritus in three (7.5%); acneic dermati-tis in three (7.5%); low tract urinary infection in two (5%); pharyngitis in one (2.5%); urticaria in one (2.5%);persistent headache in one (2.5%); eczema in one (2.5%); psoriasis in one (2.5%); erythema in one (2.5%); oral abscess in one (2.5%); acute cholangitis in one (2.5%), and shingles in one (2.5%) (Table 2). EVL discontinua- tion occurred at a mean of 34 ± 19.2 days since drug ini- Twelve months after switch, in patients successfully converted to EVL monotherapy (30/40) proteinuria (spot sample analysis) increased from a mean of Intractable pruritus (consent withdrawal) 203 ± 95.8 mg/24 h at baseline to a mean of 246 ± 54.3 mg/24 h, while the mean change of cCrCl was 4.03 ± 12.6 ml/min (range )10.6‚52.5 ml/min; 95% CI )1.8‚9.1 ml/min), i.e. from a mean of 62.3 ± 24.6 mL/ min (range 38.3–154.6) at baseline to a mean of 67.7 ± 35.9 ml/min (range 34.3)207.1 ml/min) (Table 2).
Namely, 17 patients (56.7%) improved their baseline cCrCl (Table 3); 4 (13.3%) presented no improvement (as per baseline cCrCl ± 0.9 ml/min), and 9 (30%) pre- sented deterioration of their baseline renal function despite EVL introduction (Table 3). Based on data from the international literature [2], we tested whether there was any correlation between the DcCrCl and some selected clinical variables, such as baseline cCrCl, patient’s age, time from transplantation, gender, and HCV status (Table 4). On univariate and multivariate analysis the only clinical variable correlated with the probability of cCrCl improvement 12 months after switching to EVL was the baseline cCrCl (P < 0.0001) (Table 4).
Starting on day 1, all patients were administered 1.5 mg EVL in two split doses with overnight withdrawal Table 3. Change in cCrCl at 12 months in 30 patients successfullyconverted to EVL monotherapy.
BPAR, biopsy-proven acute rejection; cCrCl, calculated creatinine clearance according to Cockroft-Gault; ULR, upper limit of the range.
*CNI elimination 6 months postswitch.
 Persistence of CNI (±EVL) 6 months postswitch.
àCholesterol >220 mg/dl and/or triglycerides >350 mg/dl.
§In the absence of signs of biliary obstruction.
–Spot sample analysis; 30 evaluable patients with no CNI.
**Thirty evaluable patients with no CNI.
Journal compilation ª 2008 European Society for Organ Transplantation 22 (2009) 279–286 Table 4. Correlation analysis between the change in cCrCl at blood levels remained quite stable by means of a slight 12 months and selected patients clinical variables.
increase in total daily dosage, attributable to CNI elimina-tion (Table 6). At 12 months, mean EVL daily dosage in patients successfully converted to EVL (30/40) was 2.1 ± 1.09 mg and mean EVL blood trough level was Table 7 illustrates the HCV viral load by follow-up visit. No significant change in baseline log viral load was observed throughout the study period, with a meanchange from baseline of 0.2 (Table 7). With respect to the of antimetabolites and a 50% per week reduction of CNI Table 6. EVL dosage and trough blood levels* by follow-up visit.
with complete stoppage within 4 weeks. No patientdropped out of EVL within 7 days after drug initiation because of any adverse effects. Seven days after conver- sion, the mean EVL trough blood level was 6.4 ± 3.9 ng/ ml in the overall population (range 1.3–15.5 ng/ml); 7.3 ± 4.2 ng/ml among patients on CsA-ME (range 2.2– 15.5 ng/ml) vs. 4.1 ± 1.6 ng/ml for patients on TAC patients (15%) were below the target range (mean 2.2 ± 0.6 ng/ml); eight (20%) were above the target range (mean 12.5 ± 2.6 ng/ml); and 26 (65%) were within the target range (mean 5.3 ± 1.3 ng/ml) (Table 5). According to their baseline immunosuppression, 7 days after EVL initiation 7.1% (2/28) patients on CsA-ME were belowthe target range as opposed to 33.3% (4/12) on TAC *FPIA; target range 3–8 ng/ml.
 Treatment failures excluded.
(P = 0.0548); 67.8% (19/28) patients on CsA-ME werewithin the target range vs. 58.3% (7/12) on TAC(P = 0.7201); and 25% (7/28) patients on CsA-ME were Table 7. HCV-RNA* by follow-up visit.
above the target range vs. 8.3% (1/12) on TAC (P = 0.3955). Seven days after EVL introduction, patients on CsA-ME had a higher probability of being above>8 ng/ml when compared with patients on TAC (OR 3.6; 95% CI 0.37–180.02), while patients on TAC had a higher probability of EVL trough blood levels <3 ng/ml (OR 6.5; 95% CI 0.72–79.82) (Table 5). Mean EVL daily dosage and mean EVL trough blood level per study visit are illus- trated in Table 6. These data are to be interpreted taking into account that CNI were being tapered within the first 4 weeks, according to the study protocol. There was a tendency towards EVL dose reduction within the first month, on account of the pharmacokinetic interaction between EVL and CNI, and the incidence of adverse *Amplicore assay. All patients were genotype 1.
events. From the second month onward, EVL trough Table 5. EVL blood trough levels*7 days after drug introduction.
ª 2008 The AuthorsJournal compilation ª 2008 European Society for Organ Transplantation 22 (2009) 279–286 Table 8. Main clinical characteristics of the three HCV-RNA positive maintenance patients. In that regard, EVL may offer patients with hypertransaminasemia after EVL introduction.
advantages for both the objectives. The assumption of thisstudy was to test the equivalence of EVL versus CNI either with or without antimetabolites in adult, maintenance LT patients with a minimum follow-up of 1 year, and a base- line CsA trough level £ 150 ng/ml (and/or C2-h £ 650 ng/ ml) or baseline TAC trough level £ 8 ng/ml. Previous clin- ical studies have already demonstrated equivalent clinical efficacy of EVL and MMF when used in combination with CsA-ME in renal transplantation, but to the best of our knowledge, no study has ever attempted at testing equiva- lence of EVL versus CNI either with or without antime- tabolites in LT. Collaterally, we also aimed at testing the impact of conversion to EVL on renal function at 12 months, as well as the mode and timing of switching from CNI to EVL because of the reported pharmacoki- netic interaction between these two categories of drugs and the risk for EVL overexposure when administered in combination with CNI. A further secondary, exploratory objective was to assess the impact of conversion on HCV viral load and HCV-related recurrent graft hepatitis by observation of the course of the disease, viremia, and liver function tests in this subset of patients.
Conversion from CNI either with or without antime- tabolites to EVL proved feasible in 75% of patients, §Performed after occurrence of hypertransaminasemia, Ishak-Knodell.
matching favorably data of preliminary experiences with –Retrospective comparison of histology after adverse event and base- SRL [18–27]. Incidence of BPAR (15%) and of adverse effects was in agreement with data for SRL with hyperli-pemia being the most frequent complication (42.5% of three HCV-RNA positive patients with hypertransaminas- LT patients of the current experience). However, we are emia (>3 ULR), Table 8 illustrates their main clinical and convinced that prevention of EVL overexposure might demographic features. All patients were on CsA as base- further increase the feasibility and safety rates of conver- line primary immunosuppressant, and 7 days after drug sion. Upon introduction of EVL in combination with a 50%-per-week reduction of baseline CNI, the likelihood 14.2 ± 1.6 ng/ml, with no increase in their log viral load.
of a drug trough level ‡ 8 ng/ml 7 days thereafter was On a retrospective basis, HCV genotype was 1 in all cases three times higher for patients on CsA-ME than for those and all patients had failed to respond to previous antiviral on TAC (Table 4). In order to reduce inadvertent EVL treatment in the post-transplant course for histology-pro- overexposure while switching from CNI to EVL, a policy ven recurrent HCV-related graft hepatitis. On occurrence of CsA-ME reduction >50% may be anticipated. In con- of hypertransaminasemia, EVL was stopped, a liver biopsy trast, patients on TAC as baseline immunosuppressant was performed, and all patients resumed their baseline had a sixfold increase in the risk for EVL trough immunosuppressive regimen with endpoint normalization level £ 3 ng/ml 7 days after switching. For these patients of liver function tests in two of them. The retrospective an initial daily dose of 2 mg or a policy of waiting for comparison of the baseline and post-adverse event histol- achievement of EVL target range before TAC withdrawal ogy revealed minimal deterioration in the grading score might be a reasonable alternative to what is reported in the current experience. We were also convinced that EVLoverexposure was responsible for the hypertransaminas-emia observed in three HCV-RNA positive patients.
Because of both interaction with CsA-ME and impaired Two major challenges are posed to the LT community, i.e.
liver metabolism secondary to the underlying recurrent developing immunosuppressive regimens that maintain graft hepatitis, EVL trough levels were >10 ng/mL in all high rates of transplantation success while reducing three patients 7 days after drug introduction, despite a adverse side-effects, and improving the quality of life in Journal compilation ª 2008 European Society for Organ Transplantation 22 (2009) 279–286 (Table 8). The fact that all these patients were genotype 1, were affected with advanced HCV-related graft hepati-tis, and had failed to respond to previous antiviral treat- PDS and FF: designed the research study, analyzed the ment may well underscore that this category of patients data. PDS, PC, SP, and FC: enrolled patients and per- might not benefit from a sudden change in their net formed the study. AP: performed the laboratory tests immunosuppressive status. A policy of reduction of base- (with special regard to everolimus trough levels). DC: the line CsA-ME or temporary switching to MMF monother- pathologist for all biopsies performed throughout the apy before EVL introduction should be tested in eventual study period. LB and JD: dispensed drugs and kept clini- clinical trials to help select the best switching strategy in cal records of follow-up visits, drug schedules and adverse HCV positive patients with recurrent graft hepatitis for events. EB and LC: collected the data. PDS: wrote the reduction of the risk of hepatitis flare.
In terms of renel function, CNI withdrawal was asso- ciated with improvement of cCrCl in 57% of patients successfully converted to EVL monotherapy. However themagnitude of improvement was lower than expected The authors owe a deep debt of gratitude to all the nurse (mean 4.03 ± 12.6 ml/min) and directly correlated with staff personnel of the Coordinamento Trapianti di Fegato patients’ baseline cCrCl rather than with age, gender, of Pisa Liver Transplantation Unit for their commitment HCV-status, and interval from transplantation. These results are in keeping with a recent experience by Cejasand co. of switching to SRL monotherapy in 112 adult LT recipients with impaired renal function (cCrCl<90 ml/min) [27]. The authors reported no significant 1. Calne RY. Immunosuppression in liver transplantation.
improvement in cCrCl (Cockroft) for patients with base- line values <40 ml/min as opposed to those with 2. Ojo A. Renal disease in recipients of nonrenal solid organ >40 ml/min. We could not find any threshold in cCrCl transplantation. Semin Nephrol 2007; 27: 498.
that correlated with the highest probability of improve- 3. Bechstein WO. Neurotoxicity of calcineurin inhibitors: ment in renal function and our data show that the extent impact and clinical management. Transpl Int 2000; 13: 313.
of change is correlated in a continuous rather than cate- 4. Mells G, Neuberger J. Reducing the risk of cardiovascular gorical way with baseline cCrCl. Some reasons to explain disease in liver allograft recipients. Transplantation 2007; this are both the long interval from transplantation (mean 5. Marchetti P. New-onset diabetes mellitus after liver trans- 45.5 ± 31.2 months) and the age of the recipients (mean plantation: from pathogenesis to management. Liver Trans- 54.9 ± 11 years) of the current experience. Therefore it seems reasonable that earlier policies (<12 months) of 6. Guerra G, Srinivas TR, Meier-Kriesche HU. Calcineurin- CNI minimization should be taken into account in the inhibitor free immunosuppression in kidney transplanta- post-transplant course to improve renal function in LT patients, based on the assumption that ‘‘the earlier, the 7. Hirose R, Vincenti F. Immunosuppression: today, tomor- better’’ after thorough evaluation of the patient immuno- row, and withdrawal. Semin Liver Dis 2006; 26: 201.
logical risk. Based on the feasibility of EVL monotherapy 8. Hirose R, Roberts JP, Quan D, et al. Experience with in maintenance LT recipients, the hypothesis of EVL daclizumab in liver transplantation: renal transplant dosing monotherapy vs. continuation of CNI-based immunosup- without calcineurin inhibitors is insufficient to prevent pression is being tested in de novo LT in an ongoing, acute rejection in liver transplantation. Transplantation In keeping with ongoing studies on the use of EVL in 9. Chapman JR, Valantine H, Albanell J, et al. Proliferation LT, conversion to EVL monotherapy is feasible and safe in signal inhibitors in transplantation: questions at the adult, maintenance LT recipients with a minimum follow- cutting edge of everolimus therapy. Transplant Proc 2007; up of one year. Issues needing further refinement include avoidence of inadvertent drug overexposure, especially in 10. Schuurman HJ, Cottens S, Fuchs S, et al. SDZ RAD, a new patients with CsA-based immunosuppression, and man- rapamycin derivative: synergism with cyclosporine. Trans- agement of drug-related adverse effects. Growing experi- ence with EVL, ongoing patient enrollment, and better 11. Hausen B, Boeke K, Berry GJ, Segarra IT, Christians U, patient profiling may help improve the feasibility and Morris RE. Suppression of acute rejection in allogenic rat safety of conversion to EVL and help patients benefit from transplantation: a study of the efficacy and pharmacokinet- the advantages of antiproliferative immunosuppression.
ics of rapamycine derivative (SDZ RAD) used alone and in ª 2008 The AuthorsJournal compilation ª 2008 European Society for Organ Transplantation 22 (2009) 279–286 combination with a microemulsion formulation of cyslosp- 21. Nair S, Eason J, Loss G. Sirolimus monotherapy in neph- orine. J Heart Lung Transplant 1999; 18: 150.
rotoxicity due to calcineurin inhibitors in liver transplant 12. Levy GA, Grant D, Paradis K, Campestrini J, Smith T, recipients. Liver Transpl 2003; 9: 126.
Kovarik JM. Pharmacokinetics and tolerability of 40-0[2- 22. Fairbanks KD, Eustace JA, Fine D, Thuluvath PJ. Renal hydroxyethyl]rapamycin in de novo liver transplant recipi- function improves in liver transplant recipients when ents. Transplantation 2001; 71: 160.
switched from a calcineurin inhibitor to sirolimus. Liver 13. Levy G, Schmidli H, Punch J, et al. Safety, tolerability, and efficacy of everolimus in de novo liver transplant recipients: 23. Morard I, Dumortier J, Spahr L, et al. Conversion to sirol- 12- and 36-month results. Liver Transpl 2006; 12: 1640.
imus-based immunosuppression in maintenance liver 14. Treeck O, Wacwitz B, Haus U, Ortmann O. Effects of a transplantation patients. Liver Transpl 2007; 13: 658.
combined treatment with mTOR inhibitor RAD001 and 24. Yang YJ, Li LX, He Q, et al. Sirolimus as primary immu- tamoxifen in vitro on growth and apoptosis of human nosuppressant for calcineurin inhibitor-related insuffi- cancer cells. Gynecol Oncol 2006; 102: 292.
ciency after liver transplantation. Hepatobiliary Pancreat 15. Mabuchi S, Altomare DA, Cheung M, et al. RAD001 inhibits human ovarian cancer cell proliferation, enhances 25. Shenoy S, Hardinger KL, Crippin J, et al. Sirolimus con- cisplatin-induced apoptosis, and prolongs survival in an version in liver transplant recipient with renal dysfunction: ovarian cancer model. Clin Cancer Res 2007; 13: 4261.
a prospective, randomized, single-center trial. Transplanta- 16. Grozinsky-Glasberg S, Franchi G, Teng M, et al. Octeotride and the mTOR inhibitor RAD001 (Everolimus) block pro- 26. Watson CJ, Gimson AE, Alexander GJ, et al. A random- liferation and interact with the Akt-mTOR-p70S6K path- ized controlled trial of late conversion from calcineurin way in a neuro-endocrine tumour cell line.
inhibitor (CNI)-based to sirolimus-based immunosuppres- Neuroendocrinology 2008; 87(3): 168.
sion in liver transplant recipients with impaired renal 17. Gomez-Camarero J, Salcedo M, Rincon D, et al. Use of function. Liver Transpl 2007; 13: 1694.
everolimus as a rescue immunosuppressive therapy in liver 27. Cejas N, Casciato P, Descalzi V, et al. Conversion from transplant patients with neoplasms. Transplantation 2007; calcineurin inhibitors (CNIs) to sirolimus (SRL) immuno- suppression is beneficial in liver transplant (LT) recipients 18. Chang GJ, Mahanty HD, Quan D, et al. Experience with with renal dysfunction (RD) [abstract]. Liver Transpl 2007; the use of sirolimus in liver transplantation-use in patients for whom calcineurin inhibitors are contraindicated. Liver 28. Cockroft DW, Gault MH. Prediction of creatinine clear- ance from serum creatinine. Nephron 1976; 16: 31.
19. Cotterell AH, Fisher RA, King AL, et al. Calcineurin inhibi- 29. Levin N, Eknoyan G, Pipp M, Staeinberg E. National Kid- tor-induced chronic nephrotoxicity in liver transplant ney Foundation: Dialysis Outcome Quality Initiative- patients is reversible using rapamycin as the primary immu- Development of methodology for practice guidelines.
nosuppressive agent. Clin Transplant 2002; 16(Suppl. 7): 49.
Nephrol Dial Transplant 1997; 12: 2060.
20. Kniepeiss D, Iberer F, Grasser B, Schaffellner S, Tscheliess- 30. Demetris AJ, Batts KP, Dhillon AP, et al. Banff schema for nig KH. Sirolimus and mycophenolate mofetil after liver grading liver allograft rejection: an international consensus transplantation. Transpl Int 2003; 16: 504.
Journal compilation ª 2008 European Society for Organ Transplantation 22 (2009) 279–286


Microsoft word - 18700 gb fastbrain jewel gram terms of use.doc

JEWELGRAM SITE TERMS OF USE The site you are visiting is (hereafter known as the “Site” ). The owners of the Site (hereafter known as the “Owners” ) are the holders of the following Terms of Use. You may use the Site if you are an individual for your personal, non commercial use, for viewing and purchasing the products marked with JewelGram brand. Such individ

La réforme canoniale à l'abbaye de saint-maurice au xiie siècle

Dans Echos de Saint-Maurice, 1959, numéro spécial, p. 42-49 On sait que l'Abbaye de Saint-Maurice a passé par des phases diverses au cours de sa longue histoire. « En suivant sa vie intérieure et l'ordre de ses réformes », écrit M. le chanoine J.-M. Theurillat, on peut diviser cette histoire « d'une façon très adéquate » en cinq périodes nettement distinctes. Voici comment

Copyright © 2010 Medicament Inoculation Pdf